A final, extended follow-up analysis of the ALPINE study has confirmed that zanubrutinib remains more efficacious than ibrutinib out to 42.5 months in patients with relapsed/refractory CLL/SLL.
The second-generation BTK inhibitor also exhibited an improved overall safety profile over the first-generation BTKi ibrutinib.
The study, published in Blood [link here], reported that the 36-month PFS rate was 65.4% in the zanubrutinib treatment arm and 54.4% in the ibrutinib treatment arm.
Improvement in PFS of zanubrutinib over ibrutinib was sustained in high-risk patients with del(17p)/TP53mut (HR: 0.51 [95% CI, 0.33-0.78] as well as in patients without del(17p)/TP53mut (HR: 0.79 [95% CI, 0.61-1.02].
ORR remained higher with zanubrutinib compared with ibrutinib at 42.5 months (85.6% vs 75.4%; RR: 1.13 [95% CI, 1.05-1.22]), the rate of PR with lymphocytosis or better was 90.2% vs 82.8%, respectively.
“While clinical responses deepened in both arms over time, zanubrutinib-treated patients reached CR/CRi earlier and more of them achieved CR/CRi than did ibrutinib-treated patients,” the study said.
Median OS had not been reached in either treatment group.
Safety
The study reported that the prevalence of most AEs has remained stable year-over-year.
The most common non-haematologic treatment-emergent AEs of any grade with zanubrutinib versus ibrutinib were COVID-19 infections (46.0% v 33.3%), upper respiratory tract infection (29.3% v 19.8%), diarrhoea (18.8% v 25.6%), and hypertension (27.2% v 25.3%).
“The most commonly reported non-haematologic grade ≥3 AEs were hypertension (17.0% vs 16.0%), COVID-19-related infections (17.9% vs 12.0%), and pneumonia (7.7% vs 10.5%), respectively.”
Neutropenia was the most common haematologic AE of any grade (31.5% vs 29.6%) and grade ≥3 (22.8% vs 22.8%) with zanubrutinib vs ibrutinib, respectively.
“Fewer zanubrutinib treated patients discontinued treatment due to AEs, and fewer patients exhibited cardiac side effects, such as atrial fibrillation,” the study said.
“Overall cardiac events remained considerably lower with zanubrutinib compared with ibrutinib and the rate of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%) despite similar hypertension rates.”
Rates of fatal AEs were comparable between treatment arms with more than half of the fatal AEs due to infections such as COVID-19 and/or pneumonia.
Insights
The investigators, including Professor Constantine Tam from the Alfred Hospital and Monash University in Melbourne, said findings usefully extend those from the primary analysis.
“With longer follow-up, the higher response rates – both ORR and CR/CRi – persisted among patients treated with zanubrutinib compared to those treated with ibrutinib,” they said.
“Similar to other phase 3 zanubrutinib studies, ALPINE demonstrated a deepening of response over time, with consistently higher CR/CRi rates in the zanubrutinib arm over the course of the study.”
Given the demonstrated superiority of zanubrutinib, the ALPINE trial has closed and patients in the ibrutinib arm have been allowed to crossover to zanubrutinib for a separate long-term extension study. [link here]
The ALPINE trial and the ongoing extension study were funded by BeiGene.